The hope of achieving high performance identification of ionic species using ion mobility drift tubes coupled with time of flight mass spectrometers has long been held by those skilled in the art. The general concept has been known since at least the publication of the paper entitled xe2x80x9cIon Mobility/Mass Spectrometric Investigation of Electrospray Ionsxe2x80x9d by R. Guevremont, K. W. M. Siu, and L. Ding in the Proceedings of the 44th ASMS Conference, p. 1090 (1996). This paper, and all other papers and patents identified herein are hereby explicitly incorporated into this disclosure by this reference. The concept was again published in the paper xe2x80x9cCombined ion mobility/time-of-flight mass spectrometry study of electrospray-generated ions. Anal. Chem. 69, 3959 (1997). The concept was. again described in the patent literature in May of 1999, when U.S. Pat. No. 5,905,258 titled xe2x80x9cHybrid ion mobility and mass spectrometerxe2x80x9d issued to David E. Clemmer, et al.
While the general concept of such systems has thus long been recognized, those having skill in the art have also recognized limitations associated with the technique when put into practice. One approach towards achieving the objective of increased sensitivity in ion mobility spectrometry/mass spectrometry (IMS/MS) instruments is described in U.S. Patent Application Pub No. 2001/0032929A1 by Fuhrer et al. wherein improvements in sensitivity are claimed as a result of preserving a narrow spatial distribution of migrating ions through the use of periodic/hyperbolic field focusing. Variations on the general IMS/MS concept are shown in U.S. Pat. No. 6,323,482 filed May 17, 1999, granted Nov. 27, 2001, xe2x80x9cIon mobility and mass spectrometerxe2x80x9d which shows the use of collision cell in an IMS/time of flight MS hybrid system and various means to incorporate the collision cell into such instrumentation. Further variations are also shown in U.S. Pat. No. 6,498,342 filed Jul. 13, 2000, granted Dec. 24, 2002 xe2x80x9cIon separation instrumentxe2x80x9d which introduces the liquid-phase separation (such as liquid chromatography) prior to IMS/time of flight MS or a tandem IMS/time of flight MS system. Finally, U.S. Pat. No. 6,559,441 filed Feb. 12, 2002, granted May 6, 2003 xe2x80x9cIon separation instrumentxe2x80x9d details various conceivable versions of tandem IMS, e.g. use of different buffer gases and/or different temperatures.
Despite these and other improvements, problems associated with loss of ions in ion mobility spectrometer (IMS) drift tubes have continued to prevent IMS/MS systems from reaching their full potential as analytical instruments. Rather, other systems with much slower separations times, but lower ion losses, such as liquid chromatography mass spectrometry (LC/MS), have prevailed despite the sample analysis xe2x80x9cthroughputxe2x80x9d reductions associated with such systems. The problem of excessive ion losses in IMS/MS systems is well known by those having skill in the art, and has repeatedly been identified in the literature by numerous researchers active in the field. For example, in the paper titled xe2x80x9cGas-phase separations of complex tryptic peptide mixturesxe2x80x9d published in Fresenius J. Anal. Chem. 369, 234 (2001), by J. A. Taraszka, A. E. Counterman and D. E. Clemmer, in the sentence bridging pages 242 and 243, the authors described one aspect of the problem thusly: xe2x80x9cCurrently one stumbling block associated with high-resolution instruments is that most signal (xcx9c99-99.9%) is discarded when the short pulse of ions is introduced into the drift tube.xe2x80x9d In the paper titled xe2x80x9cMultidimensional separations of complex peptide mixtures: a combined high performance liquid chromatography/ion mobility/time-of-flight mass spectrometry approachxe2x80x9d published in Intern. J. Mass Spectrom. 212, 97 (2001), by S. J. Valentine, M. Kulchania, C. A. Srebalus Barnes, and D. E. Clemmer, at the final paragraph on page 108, the authors again recognize difficulties with the technique stating: xe2x80x9cIt is typical to discard 99-99.9% of the ion signal during the mobility experiment [34]; thus, these experiments are inherently less sensitive than conventional LC-ESI-MS methods.xe2x80x9d Yet another paper in the literature identifying the problem is entitled xe2x80x9cCoupling ion mobility separations, collisional activation techniques, and multiple stages of MS for analysis of complex peptide mixturesxe2x80x9d, Anal. Chem. 74, 992 (2002), by C. S. Hoaglund-Hyzer, Y. J. Lee, A. E. Counterman, and D. E. Clemmer. At page 1005, the authors state: xe2x80x9cWe also note that although improvements in sensitivity have been demonstrated, the current technologies are still not as sensitive as the well-developed MS/MS strategies; however we believe that much of this difference will be diminished as additional improvements in the instruments are made. Finally, other authors, including Russell and coworkers active in the field at Texas AandM University, have repeatedly pointed out the need for much better IMS/MS sensitivity.
Thus, there remains a need for methods and apparatus that enable increased sensitivity in ion mobility spectrometry/mass spectrometry (IMS/MS) instruments and which substantially reduces the loss of ions in ion mobility spectrometer (IMS) drift tubes.
Accordingly, it is an object of the present invention to provide methods and apparatus that enable increased sensitivity in ion mobility spectrometry/mass spectrometry instruments and substantially reduce the loss of ions in ion mobility spectrometer drift tubes. These and other objects of the present invention are accomplished by providing a method and apparatus for analyzing ions utilizing an hourglass electrodynamic ion funnel at the entrance to the drift tube and/or an ion funnel at the exit of the drift tube, as shown in the cutaway schematic drawing of FIG. 1. Briefly, the present invention comprises an hourglass electrodynamic funnel 1 formed of at least an entry element 2, a center element 3, and an exit element 4, each of said elements having an aperture. The entry element 2 is aligned such that a passageway for charged particles is formed through the aperture within the entry element 2, through an aperture in the center element 3, and then through the aperture in the exit element 4. It is important that the aperture in the center element 3 is smaller than the aperture of the entry element 2 and the aperture of the exit element 4. Typically, the hourglass electrodynamic funnel 1 will consist of more than three elements, perhaps as many as several hundred elements. It is not necessary that the center element 3 be at the exact middle of all elements. In an embodiment, for example, with 100 elements, the center element 3 could be the 80th element, rendering the electrodynamic funnel asymmetric. All that is required of the center element 3 is that it be the smallest of the elements, and that the center element 3 have at least one element (the entry 2 and exit element 4) to each of both sides. Conceptually, therefore, three elements are the minimum necessary to describe and operate the invention.
The hourglass electrodynamic funnel 1 forms the entrance to a drift tube 5. Ions generated in a relatively high pressure region by an ion source 6 at the exterior of the hourglass electrodynamic funnel 1 are transmitted to a relatively low pressure region at the entrance of the hourglass funnel 1 through a conductance limiting orifice 7, which may be fashioned from, by way of example, a heated capillary. Typically, a differential pump 8 evacuates the hourglass electrodynamic funnel chamber. Alternating and direct electrical potentials are applied to the elements of the hourglass electrodynamic funnel 1 as with a standard ion funnel as described in U.S. Pat. No. 6,107,628, issued Aug. 22, 2000, and entitled xe2x80x9cMethod and apparatus for directing ions and other charged particles generated at near atmospheric pressures into a region under vacuumxe2x80x9d the entire contents of which are hereby incorporated herein by this reference, thereby drawing ions into and through the hourglass electrodynamic funnel 1. In this manner, the hourglass electrodynamic funnel 1 captures an expanding flow of ions generated in a relatively high pressure region and directs them through the small aperture of the center element 3, into the drift tube 5 which is maintained at a relatively low pressure compared to the ion generation region. The center element 3 thus defines a small aperture for the entry to the drift tube 5, and thus a conductance limit. Combined with the entry element 2, this configuration introduces relatively large quantities of ions into the drift tube 5 while maintaining the gas pressure and composition at the interior of the drift tube 5 as distinct from those at the entrance of the electrodynamic funnel 1 and allowing a positive gas pressure to be maintained within the drift tube, if desired.
The electrodynamic funnel 1 may also utilize a jet disturber 9, such as that described in U.S. Pat. No. 6,583,408, issued Jun. 24, 2003 and entitled xe2x80x9cIonization source utilizing a jet disturber in combination with an ion funnel and method of operationxe2x80x9d the entire contents of which are incorporated herein by this reference. The jet disturber 9 can be operated to prevent undesired species from entering the drift tube 5, to modulate the signal intensity, and to improve the signal to noise ratio. Additionally, the hourglass electrodynamic 1 funnel can include a further means 10 for temporarily containing the flow of ions out of the aperture of the exit element. These means could be a plurality of wires, a mesh, or a microchannel plate. Ions can be accumulated in the region between the center element 3 and the exit element 4, and by varying the potential applied to these means, pulsed through the exit element 4 at a known time, thereby allowing precise analysis of the time necessary for differing ions to pass through the flow tube. The hourglass shape of the electrodynamic funnel 1 thus allows the accumulation of much larger numbers of ions than is enabled by the conventional geometry of prior art ion funnels.
Alternatively, ions passing through electrodynamic funnel 1 may be pulsed by intermittent deflection by an electric field orthogonal to the ion path, generated by any of several means 10 known in the art, including, but not limited to, a Bradbury-Nielsen gate, two or more deflection plates, or a split lens.
While the apertures are typically circular, they may be any shape. For specific applications, for example to form ion packets having an elongated profile, and particularly a highly elongated xe2x80x9crazorxe2x80x9d profile, as is useful for field asymmetric waveform ion mobility spectrometry, photodissociation, and laser spectroscopy, ellipsoidal and rectangular apertures are preferred.
The exit of the drift tube 5, located at the opposite end of the drift tube from the hourglass electrodynamic funnel 1, is typically in communication with an ion analysis means 11, such as a mass spectrometer. While not meant to be limiting, the method and apparatus of the present invention can be in communication with a quadrupole mass spectrometer, a time of flight mass spectrometer, a Fourier-transform ion cyclotron resonance mass spectrometer, a photoelectron spectrometer, or a photodissociation spectrometer. The drift tube 5 can be an ion mobility spectrometer, a field asymmetric waveform ion mobility spectrometer, a selected ion flow tube, or a proton-transfer reaction mass spectrometer.
The present invention is capable of being interfaced with any conventional ion source 6, including but not limited to electrospray ionization, coldspray ionization, thermospray ionization, matrix-assisted laser desorption ionization, surface-enhanced laser desorption ionization, laser vaporization, and are discharge.
The present invention may also be configured as having two or more hourglass electrodynamic funnels 1 each forming a separate entrance to the drift tube 5 thereby providing two or more passageways for ions generated in a relatively high pressure region at the exterior of the drift tube 5 to a relatively low pressure region at the interior of the drift tube 5. In this manner, the ease of calibration of the present invention is enhanced.
The present invention may also be configured as a dual entry hourglass electrodynamic funnel as described in U.S. patent application Ser. No. 10/400,356, filed Mar. 25, 2003, and entitled xe2x80x9cMulti-Source Ion Funnel,xe2x80x9d, the entire contents of which are incorporated herein by this reference. As shown in the Multi-Source Ion Funnel patent application, the dual source ion funnel is formed of at least two entry elements, one center element, and one exit element, each of the elements having an aperture, and wherein each of the two or more entry elements are aligned such that a passageway for charged particles is formed through apertures within the entry elements, through an aperture in said center element, and through the aperture in the exit element, thereby providing two separate but merging passageways for ions generated in a relatively high pressure region to a relatively low pressure region. As adapted for the present invention, as with the more general case, the aperture of the exit element 5 of the dual source configuration is again larger than each of the apertures of each of the center elements 3, and the two separate but merging passageways are for ions generated in a relatively high pressure region at the exterior of a drift tube 5 to the relatively low pressure region at the interior of the drift tube 5.
In another aspect of the present invention, an internal ion funnel 12 is provided within the drift tube 5. The internal ion funnel 12 is configured as a standard ion funnel; it has at least one element 13 having a relatively small aperture and at least one element having a relatively large aperture 14. Alternating and direct electrical potentials are applied to the elements of the internal ion funnel 12 as with a standard ion funnel as described in xe2x80x9cMethod and apparatus for directing ions and other charged particles generated at near atmospheric pressures into a region under vacuum,xe2x80x9d U.S. Pat. No. 6,107,628, issued Aug. 22, 2000. As with the hourglass electrodynamic funnel 1, the internal ion funnel 12 will typically consist of more than two elements, perhaps as many as 100 elements. Conceptually, however, as is the case with the standard ion funnel, two elements are the minimum necessary to operate internal ion funnel 12. The internal ion funnel 12 is positioned at the exit of said drift tube 5 wherein the element having the small aperture 13 is positioned adjacent to the exit of drift tube 5. The internal ion funnel 12 may be used alone or in combination with any of the aforementioned variations of the hourglass electrodynamic funnel 1. The advantage of the internal ion funnel 12 is that ions that are usually dispersed away from the exit aperture within the drift tube 5, such as those that are typically lost in conventional drift tubes to any subsequent analysis or measurement, are instead focused through the exit of the drift tube 5, vastly increasing the amount of ions exiting the drift tube 5.
While the general characteristics of the present invention have been shown and described, the operation and advantages of the present invention are best illustrated by an example. Accordingly, experiments in which the present invention was reduced to practice and then operated to demonstrate the superior performance enabled by the present invention when compared to prior art methods were conducted and are described below. However, the present invention should in no way be viewed as limited to either the specific device, or the operation of that device, as described below. Rather, these experiments are provided merely to illustrate the advantages of the present invention, and to illustrate an example of how the present may be reduced to practice and operated. Those having skill in the art will readily recognize that numerous departures from the specific details of the device and its operation shown below are possible, yet would still fall well within the more general description provided above, and set forth in the appended claims.